Paraneoplastic cerebellar degeneration and opsoclonus/ataxia are nonmetastatic, neurologically devastating complications of gynecological or breast cancer. The causes of these disorders are not known. Antibodies to target neurons have been repeatedly detected in sera and CSF of affected patients, suggesting an autoimmune causation for these two disorders, but the actual mechanisms by which host immune response might cause neuronal injury have not been defined. The present proposal is based on recent data from our laboratory demonstrating antibodies to glutamate receptor subunits in sera from 8/8 women with paraneoplastic cerebellar degeneration and 2/2 women with opsoclonus/ataxia. These data are of interest since they raise the possibility that paraneoplastic neuronal injury in such patients may result from autoimmune perturbation of glutamate receptor function with resultant excitotoxic neuronal injury. The proposed investigations have three specific aims. The first of these is to determine whether antibodies to GluR subunit proteins are uniformly found in sera of patients with Type I and Type IIb antibody response as opposed to controls, as suggested by work to date, whether a similar antibody response can be detected in cerebrospinal fluid of affected patients, and whether there is evidence of intrathecal synthesis of antibodies. The second specific aim, bases on our detection of mRNAs encoding GluR1 and GluR5 in the tumor of one patient with Type I antibody response, will be to learn whether the systemic antibody response to GluR proteins found in these patients is elicited by antigens expressed by tumors of affected patients and to learn whether similar antigens are encoded or expressed in normal human tissues or tumors from neurologically normal individuals. The third specific aim of proposed experiments will be to determine whether antibodies to GluR subunit proteins cause death of cerebellar neurons in culture, whether a similar effect can be produced by patient sera, and, if so, whether cell death can be prevented by absorption of patient sera with GluR subunit proteins. It is anticipated that these experiments will further define the spectrum of antibody response in patients with paraneoplastic neurological syndromes and that they may provide fundamental information about mechanisms of central nervous system injury in human autoimmune disease.